Esters of piperazine 1, 4-diethanol



Patented Aug. 29, 1967 3,338,902 ESTERS F PIPERAZINE 1,4-DIETHANOL Gianfranco Pala, Milan, Italy, assignor to lstituto de Angeli S.p.A., Milan, Italy, a corporation of Italy Particularly preferred for their spasmolytic activity are the free bases and acid addition salts in which R represents a hydrogen atom or a methyl or ethyl group. Pharmacological tests have been carried out to illustrate the spasmolytic activity of the a-methyl-l-naphthylacetic pounds, two asymmetric carbon atoms are present and the compoundsmay also be in the meso-form.

of 17,604/64 mafter designated DA-914). The results of the tests are 4 Claims. (Cl. 260-268) as follows:

This invention relates to new N,N'-di(fl-hydroxyethyl) Spasmvlytic activity guinea-Pig ileum vitro" piperazine esters of tit-substituted l-naphthyl-acetic acids. The test was carried out in segments of guinea pig i to mventlon I provlde compounds of ileum according to the Magnus-Technique. The intestine e genera 0mm a was stimulated with standard doses of acetylcholine (1.10- g./ml.), histamine (1.10- g./ml.), BaCl (1.10- g./ml.), nicotine (2.10 g./ml.) and serotonine (1.10- g./ml.), and then the dosage of the substances able to produce a 50% inhibition of the contractions was determined. In the following table are stated the ED values H of DA-9l4 and also (for comparison purposes) of typical 0 I inhibitors for the contracting agents used, calculated ac- (in which R represents a hydrogen atom or straightcording to the method of M. F. Lockett and coll. (J. chained alkyl group containing 1 to 5 carbon atoms) Pharm. and PharmacoL, 8,18,1956).

Acetylcholine, BaClz,ED5o, Histamine, Nicotine, Serotonin,

D50, g./ml. g./n1l. ED, g./ml. ED n, g./rn1. EDW, g./ml.

Dix-914 3 9.10- 3 9.10- 4.10- 3 7.10 4 1.10- Diphenhydramine hydrochloride s s s 8. 3. l0- Papaverine hydrochloride s s 5 1.10- Atropin sulphate 5. 510-D Hexamethonium bitartrate" 12. 6. 10-

and monoand di-acid addition salts thereof, the anions As can be seen from these results, DA-914 is 203 times associated with said salts being physiologically acceptable more active than papaverine and 42 times more active at the effective dosage of the compounds. than hexamethonium bitartrate.

The compounds according to the invention possess pars asmolytic activity onguinea-pig ileum in vivo ticularly valuable spasmolytic activity of the myolytic The test was carried out according to the method of type which is generally more pronounced than that of Brock and coll (Arch Exp Path Pharmacol 215 512 known compounds of related structure. The spasmolytic 1952) modified by p g Exp lher 130 activity m y be detmnstrated in vitro on Segments of 356, 1 960). The contractions were produced, every rmin gum.ea'p1g lleilm Simulated by banum i acetyl utes, by perfusion of the peritoneum with BaCl solution F f and hlstamme' i compounds. i to the at the concentration of 10 mg./l. The perfusion was of 30 mventlon also y reiatwely low.toxlclty i for 45 seconds duration and the intestinal movements were reample the m mlce. of i .dlhydmchlonflie the corded by means of a water manometer. The compound a'methyu'naphthyl. acetlc acld .dlester to be tested was injected, intravenously, at various dosage droxyethyl)'pl.perazl.ne by the mtrapentoneal and oral levels 75 seconds prior to the perfusion. As a means of unites respefztlvely. i and 1600 mgJkg" comparison it was preferred to administer ethaverine hywhlle chrome toxlclty tests showed that .rats P drochloride rather than papaverine because of the fore.rate 50 of the above hydrochlonde wlthout mers lower toxicity. The dose inhibiting to a 50% degree 'tlceable effect 9 groyvth'curVe? effects on the organs the contractions produced by BaCl was calculated as in detectable by hlstologlcal p' the previously described in vitro test. The results are given The compounds according to the invention are colourin the following table, less crystalline solids. The free bases are insoluble in water and soluble in alcohol whilst the acid addition salts are sparingly soluble in alcohol and very moderately Dose figggtg g of EDS, soluble in water. Particularly preferred compounds acs-l a/ commotion a/ scording to the invention, by virtue of their high spasmo- 8 3 13??? lytic activity, are those compounds of Formula I in which R represents a lower alkyl group containing 1 to 3 carbon 5 36 atoms. The salts according to the invention may be 1311414 5- i formed by treating the free base with an acid, for exam- 5 25 ple a hydrohalic acid such as hydrochloric or hydro- Ethaverifle Y $2 10.8 bromic acid, phosphoric acid, sulphuric acid, methane sul honic acid or methane-disulphonic acid. It will be appre ziated that where R is other than hydrogen the comspasmolyflc acnvlty mt mews m Wtro pounds possess asymmetric carbon atoms and may exist The rat uterus was prepared according to the method in optically active or racemic forms all of which forms described by Burn (Biological Standardisation, Oxford are comprised within the present invention. In such com- University Press, London, 1950 (page 177). The organ was stimulated, every 3 minutes, with oxytocine and BaCl at the final concentration of 2.1(H I.U./ml. and 1.10?

Oxytocine, Bach,

ED mg./rnl. EDm, rug/m1.

DA-914 1. 9. I 2. 0. 10- Papaverine hydrochloride 1. 1. 10- 9. 8. 10-

According to a still further feature of the invention, I provide compositions comprising one or more compounds according to the invention in association with a pharmaceutical carrier or excipient.

The compositions according to the invention may be adapted for oral, rectal or parental administration, advantageously in the form of dosage units, each dosage unit being adapted to supply a single dose of active ingredient. The dosage units of the compositions according to the invention may for example take the form of tablets, dragees, capsules, suppositories or ampoules. Other convenient forms of compositions according to the invention include suspensions, syrups. etc. The pharmaceutical carriers or excipients in the compositions may for example be those conventional in the art, for example tabletting excipients, capsule gelatin, suppository bases, water, edible oils, fiavouring, sweetening, odour-producing, suspending, dispersing or thickening agents and the like.

The free bases and acid addition salts according to the invention are preferably present in the dosage unit preparations in quantities of from 1 to 200 mg., advantageously 10 to 100 mg, per dosage unit.

The free bases of Formula I provided by the present invention are insoluble in water Whilst acid addition salts thereof, such as the hydrochloride, hydrobromide, sulphate and phosphate acid addition salts, are only very moderately soluble in water yielding aqueous solutions with low pH, for example of from 2 to 3. This is advantageous where pharmaceutical compositions in the form of, for example, injectable solutions are to be prepared. One advantageous form of compositions according to the invention comprises, therefore, one or more compounds according to the invention together with a solubility promotor. Such compositions according to the invention may, for example be in the form of a solid mixture suitable for addition to distilled water to form an injectable solution or in the form of the injectable solution itself.

Solubility promoters are compounds which have the effect of increasing the solubility in water of sparingly soluble compounds and are in general well-known in the art. One class of compounds which may conveniently be used as solubility promoters are compounds having a group, especially amides and derivatives thereof. Among the solubility promoters of this class which may be used in accordance with the invention are included metamizole (sodium 1 phenyl 2,3 dimethyl 5 pyrazolone 4- methylaminomethane sulphonate), urea, nicotinarnide, nicotinamide ascorbate, piperazine, urotropine .(hexamethylene-tetramine), antipyrene, acetamide, dimethylacetamide and coramine. Particularly useful solubility promoters of this class include metamizole, nicotinamide and acetamine. A second class of compounds which may conveniently be used as solubility promoters are compounds having a -OCH -CH(OH)CH OH group, especially 3-(substituted phenoxy)-1,2-propanediols. Examples of compounds of this class include 3-(2-methoxy-phenoxy) -1,2-propanediol,

3- 2-methoxy-4-propionyl-phenoxy l ,2-propanediol, I 3- 2-methyl-4-propionyl-phenoxy) -1 ,2-propanediol, and 3- (2-chloro-4-propionyl-phenoxy) -1 ,2-propanediol.

Particularly useful compounds of this class are 3-(2-methoxy-phenoxy) 1,2 propanediol and 3-(2-methoxy-4-propionyl-phenoxy)-1,2-propanediol. Injectable solutions prepared in this way in general have sufficient thermal stability to withstand the necessary sterilisation, whilst dilution of the solutions may result in the precipitation of the compounds according to the invention in an insoluble form.

The use of solubility promoters may, according to the nature of the solubility promoters, also result in an increase in the pH of injectable solutions. Thus, the ocmethyl-naphthylacetic acid diester of N,N'-di-(B-hydroxyethyl)-piperazine dihydrochloride has a solubility of 0.5% by weight yielding an aqueous solution having a pH of about 2.5, whilst the use of metamizole as solubility promoter makes possible the preparation of aqueous solutions containing 5% by Weight of the diester and having a pH of about 5.5.

Injectable solutions according to the invention containing solubility promoters may for example be prepared by addition of one or more compounds according to the invention (preferably in the form of acid addition salts e.g. dihydrochlorides) to an aqueous solution containing the solubility promoter. The addition may be effected for example at room temperature with continuous stirring. The solubility promoter is generally used in excess, for example four to fifty times the weight of the compound according to the invention.

The compounds according to the invention may be prepared by any convenient method, for example by reaction of a piperazine derivative of the formula with a l-naphthylacetic acid derivative of the formula (the group R being as defined above and X and Y representing groups able to react together to form divalent --OCH -CH radicals) and, if desired, conversion of the compound of Formula I thereby obtained into a monoor di-acid addition salt thereof.

The compounds are particularly advantageously prepared by any one of the following processes which constitute further features of the invention.

(A) An acid halide, preferably the chloride, of an int-substituted or unsubstituted l-naphthyl acetic acid is reacted with N,N'-di-(fi-hydroxyethyl)-piperazi ne. The reaction is preferably carried out in the presence of an acid-binding agent, such as an inorganic base, e.g. sodium or potassium carbonate or bicarbonate, or a tertiary amine such as pyridine, dimethylaniline, N-methylmorpholine etc., advantageously under substantially anhydrous conditions in an inert solvent medium. Examples of suitable solvents which may be used are hydrocarbon solvents such as benzene, xylene or toluene, ethers such as diethyl ether or dioxan, and inert liquid nitriles such as acetonitrile. The reaction is conveniently effected under reflux at the boiling point of the solvent. The acid halides of the l-naphthyl acetic acids used as starting materials are conveniently prepared by reacting the free acid with a halogenating agent, such as, e.g. thionyl chloride or phosphorus oxychloride. The preparation of various mono-ot-substituted l-naphthyl acetic acids is described in our copending application No. 6,772/ 62.

(B) A fi-haloethyl ester, preferably the /3-chloroethyl ester of an a substituted or unsubstituted 1 naphthyl acetic acid is reacted with piperazine advantageously in the presence of a solvent. An acid-binding agent may conveniently be present for example an inorganic base, such as an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium bicarbonate or potassium or calcium carbonate. Suitable solvents which may be used include, for example, hydrocarbon solvents such as benzene or toluene, alcohols such as ethanol or methanol and ethers. The reaction is conveniently carried out under reflux at the boiling point of the solvent.

(C) Transesterification of esters, preferably alkyl esters of a-substituted or unsubstituted l-naphthyl acetic acids with N,N'-di-(;3-hydroxyethyl) piperazine, preferably in the presence of a transesterification catalyst such as an alkali metal hydroxide, amide etc. or strong organic or inorganic acids, e.g. sodium hydroxide or amide, ptoluene sulphonic acid or sulphuric acid. The reaction is preferably carried out under substantially anhydrous conditions in a solvent medium, such as, for example, a hydrocarbon solvent e.g. benzene or toluene. The alcohol which is formed during the reaction is preferably removed by distillation. The esters of the u-substituted or unsubstituted l-naphthyl acetic acids are conveniently prepared f-rom the free acids by conventional methods of esterification.

(D) An alkali metal salt, preferably the sodium salt, of an u-substituted or unsubstituted l-naphthyl acetic acid is reacted with an N,N-di-(fi-haloethyhpiperazine, preferably N,N-di- (fl-chloroethyl) piperazine, advantageously in the presence of a solvent medium such as, for example, an alcohol e.g. methanol, ethanol or iso-propanol, a hydrocarbon solvent such as benzene or toluene or an ether such as diethyl ether or dioxan.

For the better understanding of the invention, the following examples are given by way of illustration only;

EXAMPLE 1 (a) Preparation acid chlorides 0f a-substituted-I- naphthyl acetic acids.--l -g. of a-methyl-l-naphthylacetic acid were refluxed with 50 ml. of thionyl chloride during '3 hours. The excess thionyl chloride was removed under reduced pressure and the product was also isolated by distillation under reduced pressure. Yield: 15.6 g. (96%). The ot-methyl-l-naphthyl acetyl chloride boils at 120124 C./O. 1 mm.

The following acid chlorides were also prepared by this method;

(b) 3.52 g. of N,N-di-(fi-hydroxyethyl)-piperazine, 2.8 g. of sodium bicarbonate and 8.90 g. of u-methyl-lnaphthyl acetyl chloride were refluxed with stirring during 5 hours in 60 ml. of anhydrous benzene. After cooling the 1.76 g. of N,N'-di (fi-hydroxyethyl)-piperazine, 1.9 g. of sodium bicarbonate and 4.45 g. of a-methyl-l-naphthylacetyl chloride in 30 ml. of anhydrous acetonitrile were refluxed with stirring during 5 hours.

After cooling the mixture was filtered and the acetoni- 'trile evaporated off under reduced pressure. 5.2 g. of crude ester were obtained. The ester was converted into the hydrochlorideby the method described in Example 1. Yield 5.21 g. (84%), M.P. 220-221 C.

EXAMPLE 3 18.5 g. of a-propyl-l-naphthylacetic acid, .100 ml. of methyl alcohol and 3 ml. of concentrated sulphuric acid were refluxed during 3 hours. After cooling the solution was concentrated under reduced pressure, poured into water and extracted with ether. Upon dis-tillation under reduced pressure 14.45 g. of vat-propyl-l-naphthylacetic acid methyl ester were obtained, boiling at 133-135" C./0.8 mm.

7.05 g. of a-propyl-l-naphthylacetic acid methyl ester, 2.5 g. of N,N-di-( 8-hydroxyethyl)-piperazine, l g. of sodium amide and 45 ml. of anhydrous benzene were reacted. in a distillation apparatus provided with a reflux condenser. Methyl alcohol was removed by distillation and,'simultaneously, a further 25 ml. of anhydrous benzene were added. The solution was cooled after 4 hours, decomposed with iced water and extracted with ether. After evaporation of the solvent, 7g. of crude ester were obtained which was converted into the hydrochloride as described in Example 1. Yield 6.88 g. (72% calculated on the methyl ester). M.P. 213-214" C. 1

EXAMPLE 4 hydrochloride by the method described in Example 1.

Yield 3.35 g. (55%). M.P. 220-22l C.

EXAMPLE 5 10 ml. of pyridine were added dropwise during 10 minutes into a solution of 10 g. ot-propyl-l-naphthylacetyl chloride and 3.5 g. of ethylene chlorohydrin in 50 ml. of

anhydrous benzene. The reaction mixture was refluxed with stirring during 3 hours. After cooling, the mixture was filtered and the benzene evaporated off under reduced pressure. The residue was distilled under reduced pressure. 8 g. of a-propyl-l-naphthylacetic acid p-chloroethyl ester were obtained, boiling at -168" C./0.9 mm. 5.8 g. of u-propyl-l-naphthylacetic acid fi-chloroethyl ester, 1.9 g. of piperazine hydroxide and 1.7 g. of sodium bicarbonate in 20 ml. of ethyl alcohol were refluxed during 24 hours. The mixture was cooled, filtered and the alcohol evaporated ofi. The residue was taken up in ether, the ethereal solution filtered and the ether evaporated off. 6 g. of crude ester were obtained, which was converted into the hydrochloride as described in Example 1. Yield 3.35 g. (50%, calculated on the B-chloroethyl ester), M.P. 213-214 C.

The following compounds of general Formula I were also prepared by the method of Example 1.

Analysis Yield, R in FormulaI Empirical Formula Percent M.P., C. C H N Percent Percent Percent H C3ZH34N2O42HCI 83 232-233 FOlllld. 74 6. 17 4. 73 Calm- 65. 86 6.22 4. 80 01115 CaeHqzNzOmZEI Cl 88 236-237 FOllIld 67. 82 6. 87 4. 29 Cale 67. 59 6.93 4.38 n C3H7 CaaH4 NzO4.2HCl 84 213-214 Found 68. 46 7. 31 4.. 25 Cale as. 35 7. 24 4.19 n-C Hg C H qNzO4.2HCl 83 208-210 Found 69. 13 7. 62 3. 98 Cale 69. 05 7. 53 4. 02

7 EXAMPLE '6 into moulds and allowed to cool. Each suppositor contains Tablets: Formulation for the preparation of 1000 units. OOSO and respectlvely of awve Substance' G EXAMPLE 10 a-Methyl-l-naphthylacetic acid diester of N,N'-di- (fi-hydroxyethyl)-piperazine dihydrochloride Lactose 150 Corn starch s 23 Magnesium stearate 2 Preparation: The active substance, exci'pients and half of the magnesium stearate are intimately mixed. The homogeneous mixture is then formed into pellets which are granulated. The remaining magnesium stearate is added to the granulate and pressed into convex tablets Weighing 200 mg. Each tablet contains 25 mg. of active substance.

EXAMPLE 7 Dragees: Formulation for the preparation of 1000 units. G. u-Ethyl-l-naphthylacetic acid diester of N,N'-di- (B-hydroxyethyl)-piperazine dihydrochloride 25 Lactose 100 Corn starch 23 Magnesium stearate .....i 2 Sucrose .150

Gum-arabic, colour, distilled water, q.s.

Preparation: Prepare convex tablets as described in the previous example weighing 150 mg. The obtained tablets are then covered with sucrose syrup, gum-arabic and colour until reaching the weight of 300 mg. Each dragee contains 25 mg. of active substance.

EXAMPLE 8 Syrup: Formulation for the preparation of 1 litre.

- G. a-Methyhl-naphthylacetic acid diester of N,N-di-(;8-

'hydroxyethyl)-piperazine dihydrochloride 5 Gum tragacanth 5 Polyoxyethylene sorbitan monolaurate 5 Flavour and colour, q.s. Sucrose syrup at 50%,. q.s. for 1 litre.

Preparation: The ingredients are dissolved at a temperature of 40 to 50 C. After cooling the solution is adjusted to the required volume. Each teaspoonful (5 ml.)

contains 25 mg. of active substance.

EXAMPLE 9 Suppositories Formulations for the preparation of 1000 suppositories:

i l sa-Methyl-1-naphthylacetie acid diester of N,N-

di(fl-hydroxyethyl)-piperazine dihydrochloride" 25 5O Cocoa butter (or glycerides of saturated fatty acids, q.s. t0 2 2 The well crushed active substance is incorporated into the melted excipient. The homogeneous mixture is filled Formulations for the preparation of 1000 vials of 1 cc. volume:

Metamizole 500 u-Methylal-naphthylacetic acid diester of N,N'-di- (B-hydroxyethyl)-piperazine dihydrochloride 25 Bidistilled water, q.s. to 1 litre.

EXAMPLE 11 Formulations for the preparation of 1000 Vials of 3 cc. volume:

Metamizole 1250 u-Methyl-l-naphthylacetic acid diester of N,N'-di- (,B-hydroxyethyl)-piperazine dihydrochloride 25 Bidistilled water, q.s. to 3 litre.

Vials are prepared by a method analogous to that described in Example 10. Each vial contains 25 mg. of active substance.

EXAMPLE 12 Formulations for the preparation of 1000 vials of 1 cc. volume:

N lcotinamide 200 g. 200 g. a-Methyl-l-naphthylacetic acid diester of N,N- di-(fl-hydroxyethyl)-piperazine dihydrochloride. 25 g. 50 g. Bidistilled water, q.s. to 1 l. 1 1.

Vials are prepared from compositions A and -B respectively by a method analogous to that described in Example 10. Each vial contains 25 and 50 mg., respectively of active substance.

EXAMPLE 13 Formulations for the preparation of 1000 vials of 2 cc. volume:

Acetamide 300 a-Methyl-l-naphthylacetic acid diester of N,N-di- (p-hydroxyethyl)-piperazine dihydrochloride .v 25

Bidistil-led water, q.s. to 2 litre.

Vials are prepared by a method analogous to that described in Example 10. Each vial contains 25 mg. of active substance.

9 EXAMPLE 14 Formulations for the preparation of 1000 vials of 1 cc. volume:

G. a-Methyl-l-naphthylacetic acid diester of N,N'-di- (fl-hydroxyethyl) piperazine dihydrochloride 25 3 (2 methoxy-4-propionyl-phenoxy) 1,2propanediol 100 N,N-di-([3-hydroxyethyl)-piperazine Bidistilled water, q.s. to 1 litre.

The active substance is added to the solution obtained by dissolution of the 3-(2-methoxy-4-propionyl-phenoxy)- 1,2-propanediol in about three quarters of the indicated quantity of water. The mixture is stirred until complete dissolution is achieved and then the pH of the solution is adjusted to 4 to 5 by addition of the N,N di-(;3-hydroxyethyD-piperazine. The solution is made up to the required volume with the remainder of the water and poured into Vials which are then sealed and sterilised. Each vial contains 25 mg. of active substance.

EXAMPLE 15 Formulations for the preparation of 1000 vials of 2 cc. volume:

' G. a-Methyl-l-naphthylacetic acid diester of, N,N'-di- (,B-hydroxyethyl)-piperazine dihydrochloride 25 3-(2-methoxy-phenoxy)-1,2-propanediol 100 N,N-di-( 3-hydroxyethyl)-piperazine 5 Bidistilled water, q.s. to 2 litre.

Vials are prepared by a method analogeous to that described in Example 14.

10 What I claim is: 1. A compound selected from the group consisting of a compound of the formula wherein R is a member selected from the group consisting of hydrogen and straight-chained alkyl of from 1 to 5 carbon atoms and monoand di-acid addition salts thereof, the anions of said salts being physiologically acceptable.

2. A compound as claimed in claim 1 wherein R is straight-chained alkyl of from 1 to 3 carbon atoms.

3. A compound as claimed in claim 1 in which R is alkyl of no more than 2 carbon atoms.

4. A compound as claimed in claim 1 which is an acid addition salt selected from the group consisting of a hydrochloride, hydrobromide, phosphate, sulphate, methanesulphonate, and methanedisulfonate.

References Cited UNITED STATES PATENTS 2,995,554 8/1961 Biel 2-60-268 2,996,506 8/1961 Gold-Aubert 260 268 A-LEX MAZEL, Primary Examiner.

HENRY R. JILES, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA 